Is DYSF p.Pro1450His (c.4349C>A) pathogenic?

DYSF p.Pro1450His (c.4349C>A) is classified Uncertain significance in DYSF (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-11-25). AlphaMissense: ambiguous (0.3697); Ultra-rare (popmax 0.0149%, nfe); Associated with neuromuscular disease caused by qualitative or quantitative defects of dysferlin.

How common is DYSF p.Pro1450His (c.4349C>A) in the general population?

DYSF p.Pro1450His (c.4349C>A) is ultra-rare (popmax 0.0149%, nfe) (gnomAD).

What do computational predictors say about DYSF p.Pro1450His (c.4349C>A)?

AlphaMissense predicts ambiguous (score 0.3697) — an in-silico prediction, not a clinical call.

DYSF p.Pro1450His

Q: What condition is associated with DYSF p.Pro1450His (c.4349C>A)?

DYSF p.Pro1450His (c.4349C>A) is associated with neuromuscular disease caused by qualitative or quantitative defects of dysferlin (ClinVar).

c.4349C>A · rs142776870 · VCV2036638

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3697 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0149%, nfe)

Conditions

neuromuscular disease caused by qualitative or quantitative defects of dysferlin

Computational evidence

Protein change
AlphaMissense	0.3697	ambiguous
REVEL	0.435	indeterminate
SaProt	LLR -11.81	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 2, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 117 kb · p 0.28 · regional, not allelic
Overall
CADD	22.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P1432H vs ClinVar P1450H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0149% European (non-Finnish) · 176/1,180,012 alleles

Filtering AF 0.0131% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0124%

Overall 0.0117% 189/1,614,014 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0149%	6,705
Remaining individualsnot grpmax-eligible	0.0112%	8,926
Finnishnot grpmax-eligible	0.00781%	12,808
African / African-American	0.00133%	74,936

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: DYSF
Protein: p.Pro1450His
Coding: c.4349C>A
MANE Select: NM_001130987
dbSNP: rs142776870
Type: single nucleotide variant
Location: chr2:71612768 (GRCh38)
Gene constraint: LOEUF 0.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25 · 11 PDB

Full DYSF gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neuromuscular disease caused by qualitative or quantitative defects of dysferlin — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DYSF p.Pro1450= Likely benign ★ same residue
DYSF c.1003-3C>A Pathogenic ★★★ same condition
DYSF c.1033+1G>A Pathogenic ★★★ same condition
DYSF c.1033+4A>T Likely pathogenic ★★★ same condition
DYSF c.1149+1G>A Pathogenic ★★★ same condition
DYSF c.1149+4A>G Pathogenic ★★★ same condition
DYSF c.1276+5G>A Pathogenic ★★★ same condition
DYSF c.1276+5G>C Pathogenic ★★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/dysf-p-pro1450his (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown